Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations.

-Baroreflex responses to changes in arterial pressure are impaired in spontaneously hypertensive rats (SHR). Mean arterial pressure (MAP), heart rate (HR), and regional vascular resistances were measured before and during electrical stimulation (5-90 Hz) of the left aortic depressor nerve (ADN) in conscious SHR and normotensive control rats (NCR). The protocol was repeated after ␤-adrenergic-receptor blockade with atenolol. SHR exhibited higher basal MAP (150 Ϯ 5 vs. 103 Ϯ 2 mmHg) and HR (393 Ϯ 9 vs. 360 Ϯ 5 beats/min). The frequency-dependent hypotensive response to ADN stimulation was preserved or enhanced in SHR. The greater absolute fall in MAP at higher frequencies (Ϫ68 Ϯ 5 vs. Ϫ38 Ϯ 3 mmHg at 90-Hz stimulation) in SHR was associated with a preferential decrease in hindquarter (Ϫ43 Ϯ 5%) vs. mesenteric (Ϫ27 Ϯ 3%) resistance. In contrast, ADN stimulation decreased hindquarter and mesenteric resistances equivalently in NCR (Ϫ33 Ϯ 7% and Ϫ30 Ϯ 7%). Reflex bradycardia was also preserved in SHR, although its mechanism differed. Atenolol attenuated the bradycardia in SHR (Ϫ88 Ϯ 14 vs. Ϫ129 Ϯ 18 beats/min at 90-Hz stimulation) but did not alter the bradycardia in NCR (Ϫ116 Ϯ 16 vs. Ϫ133 Ϯ 13 beats/min). The residual bradycardia under atenolol (parasympathetic component) was reduced in SHR. MAP and HR responses to ADN stimulation were also preserved or enhanced in SHR vs. NCR after deafferentation of carotid sinuses and contralateral right ADN. The results demonstrate distinct differences in central baroreflex control in conscious SHR vs. NCR. Inhibition of cardiac sympathetic tone maintains reflex bradycardia during ADN stimulation in SHR despite impaired parasympathetic activation, and depressor responses to ADN stimulation are equivalent or even greater in SHR due to augmented hindquarter vasodilation. spontaneously hypertensive rats; arterial pressure; heart rate; atenolol BARORECEPTOR AFFERENT SENSITIVITY (1, 2, 19, 43) and baroreflex-mediated changes in heart rate (HR) (25, 38) are consistently impaired in spontaneously hypertensive rats (SHR). More controversial is baroreflex control of sympathetic nerve activity, which has been reported to be impaired (8, 10), preserved (22,33,46), or augmented (46) in SHR. The inconsistent findings may reflect, in part, differential baroreflex control of sympathetic activity to different regions and use of anesthesia in many of the studies. In the majority of studies, baroreflex responses were measured in response to drug-induced changes in arterial blood pressure (BP), which does not allow assessment of reflex changes in vascular resistance.The goal of the present study was to compare the magnitude of reflex responses to electrical stimulation of baroreceptor afferents in the aortic depressor nerve (ADN) in conscious normotensive control rats (NCR) and SHR. This approach allowed us to assess not only the fall in HR but also the decrease in BP and regional vascular resistances. Furthermore, we hypothesized that electrical activation of baroreceptor afferents would more eff...

Humans ascending to high altitudes are submitted to sustained hypoxia (SH), activating peripheral chemoreflex with several autonomic and respiratory responses. Here we analyzed the effect of short-term SH (24 h, FIO 2 10%) on the processing of cardiovascular and respiratory reflexes using an in situ preparation of rats. SH increased both the sympatho-inhibitory and bradycardiac components of baroreflex and the sympathetic and respiratory responses of peripheral chemoreflex. Electrophysiological properties and synaptic transmission in the nucleus tractus solitarius (NTS) neurons, the first synaptic station of afferents of baroreflexes and chemoreflexes, were evaluated using brainstem slices and whole-cell patch-clamp. The second-order NTS neurons were identified by previous application of fluorescent tracer onto carotid body for chemoreceptor afferents or onto aortic depressor nerve for baroreceptor afferents. SH increased the intrinsic excitability of NTS neurons. Delayed excitation, caused by A-type potassium current (IK A ), was observed in most of NTS neurons from control rats. The IK A amplitude was higher in identified second-order NTS neurons from control than in SH rats. SH also blunted the astrocytic inhibition of IK A in NTS neurons and increased the synaptic transmission in response to afferent fibers stimulation. The frequency of spontaneous excitatory currents was also increased in neurons from SH rats, indicating that SH increased the neurotransmission by presynaptic mechanisms. Therefore, short-term SH changed the glia-neuron interaction, increasing the excitability and excitatory transmission of NTS neurons, which may contribute to the observed increase in the reflex sensitivity of baroreflex and chemoreflex in in situ preparation.

The baroreflex is a critical physiological mechanism controlling cardiovascular function by modulating both the sympathetic and parasympathetic activities. Here, we report that electrical activation of the baroreflex attenuates joint inflammation in experimental arthritis induced by the administration of zymosan into the femorotibial cavity. Baroreflex activation combined with lumbar sympathectomy, adrenalectomy, celiac subdiaphragmatic vagotomy or splenectomy dissected the mechanisms involved in the inflammatory modulation, highlighting the role played by sympathetic inhibition in the attenuation of joint inflammation. From the immunological standpoint, baroreflex activation attenuates neutrophil migration and the synovial levels of inflammatory cytokines including TNF, IL-1β and IL-6, but does not affect the levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effects of the baroreflex system are not mediated by IL-10, the vagus nerve, adrenal glands or the spleen, but by the inhibition of the sympathetic drive to the knee. These results reveal a novel physiological neuronal network controlling peripheral local inflammation.

Changes in mean arterial pressure (MAP), heart rate (HR), and vascular resistance (hindquarter and mesenteric territories) in response to electrical stimulation (ES) of the aortic depressor nerve (ADN) were evaluated in conscious freely moving rats. Platinum electrodes were implanted into the ADN of all rats studied, and some of these animals were also implanted with miniaturized Doppler probes around the superior mesenteric artery and inferior abdominal aorta (hindquarter). In both groups, the femoral artery and vein were catheterized one day before the experiments. In the first group of rats ( n = 7), the control ES of the ADN in the range from 0.5 to 3.0 V (50 Hz, 10 ms) produced bradycardia and hypotension in an intensity-dependent manner, and treatment with methylatropine (intravenously) blocked the bradycardia but produced no significant changes in the hypotensive response. In a second group ( n = 6), ES of the ADN was performed with the intensity fixed at 3 V and the frequency of the stimuli varying from 10 to 50 Hz. In this group, the hypotensive response was frequency dependent, whereas the bradycardic response was not. In a third group of rats ( n = 6), ES of the ADN (2.5 V) produced hypotension (−35 ± 4 mmHg), minor changes in the mesenteric (+5 ± 14%), and vasodilation in hindquarter (−32 ± 6%) vascular beds. The data show that 1) ES of the ADN produces a fall in pressure, bradycardia, vasodilation in the hindquarter, and no changes in the mesenteric vascular resistance, 2) methylatropine blocked the bradycardia and produced no effect on the hypotensive response to ES of the ADN, and 3) the baroreceptor afferent fibers involved in the hypotensive response to ES of ADN are sensitive to the variation of the frequency of the stimuli, whereas the fibers involved in the bradycardic response are not.